[go: up one dir, main page]

EP1318995B1 - Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih - Google Patents

Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih Download PDF

Info

Publication number
EP1318995B1
EP1318995B1 EP01980812A EP01980812A EP1318995B1 EP 1318995 B1 EP1318995 B1 EP 1318995B1 EP 01980812 A EP01980812 A EP 01980812A EP 01980812 A EP01980812 A EP 01980812A EP 1318995 B1 EP1318995 B1 EP 1318995B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
het
alkyloxy
amino
mono
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP01980812A
Other languages
German (de)
English (en)
Other versions
EP1318995A2 (fr
Inventor
Jérôme Guillemont
Abdellah Benjahad
Dominique Mabire
Chi Hung N'guyen
David Grierson
Claude Monneret
Emile Bisagni
Gérard Sanz
Laurence Decrane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Institut Curie
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut Curie
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Institut Curie filed Critical Centre National de la Recherche Scientifique CNRS
Priority to EP01980812A priority Critical patent/EP1318995B1/fr
Publication of EP1318995A2 publication Critical patent/EP1318995A2/fr
Application granted granted Critical
Publication of EP1318995B1 publication Critical patent/EP1318995B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention is concerned with pyridinone and pyridinethione derivatives having Human Immunodeficiency Virus (HIV) replication inhibiting properties. It further relates to processes for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection.
  • HIV Human Immunodeficiency Virus
  • WO 86/01815 discloses the synthesis of monoazodyes and their use as dyestuffs.
  • Can. J. Chem., 1980, 58 (5), 501-526 discloses the chemistry of aurodox and related antibiotics.
  • WO 97/05113 discloses 4-aryl-thio-pyridin-2(1H)-ones and their use for treating HIV related diseases.
  • WO 99/55676 discloses 3-(amino- or aminoalkyl)pyridinone or pyridinethione derivatives and their use for the treatment of HIV related diseases.
  • thiopyridinones disclosed in WO 97/05113 have a 50% inhibitory concentration of virus multiplication (IC 50 ) for nevirapine resistant strains of about 260 nM, whereas the free amino or aminoalkyl pyridinone and pyridinone derivatives disclosed in WO 99/55676 have a 50% inhibitory concentration of virus multiplication for nevirapine resistant strains of more than 10 000 nM.
  • the inventors have found a new family of pyridinones and pyridinethiones derivatives which show better HIV inhibitory properties.
  • C 1-4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like;
  • C 1-6 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C 1-4 alkyl and pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like;
  • C 2-4 alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing a double bond such as ethenyl, propenyl, butenyl and the like;
  • C 2-6 alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing
  • halo is generic to fluoro, chloro, bromo and iodo.
  • polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl;
  • polyhaloC 1-6 alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C 1-6 alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like.
  • more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC 1-6 alkyl, they may be the same or different.
  • the R 1 or Het 1 , Het 2 , Het 3 , Het 4 or Het 5 radical as described above for the compounds of formula (I) may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate.
  • Het 1 when Het 1 is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • Lines drawn into ring systems indicate that the bond may be attached to any suitable ring atom.
  • any variable e.g. aryl
  • each definition is independent.
  • stereochemically isomeric forms as used herein before defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess.
  • chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N -oxides, salts, solvates, quaternary amines substantially free, i.e.
  • stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans -configuration.
  • Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond.
  • Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.
  • salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic) malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzensulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, din-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, thiehylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • salt forms can be converted by treatment with acid into the free acid form.
  • addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form.
  • solvates are for example hydrates, alcoholates and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Counterions include chloro, bromo, iodo, trifluoroacetate and acetate.
  • the counterion of choice can be introduced using ion exchange resins.
  • a special group of compound contains those compounds of formula (I) wherein Q is halo;
  • X is a bivalent radical of formula -(CH 2 ) p - (a-1) or -(CH 2 ) q -Z-(CH 2 ) r - (a-2); wherein p is an integer of value 1 to 5; q is an integer of value 0 to 5; r is an integer of value 0 to 5;
  • a special group of compound contains those compounds of formula (I) wherein Q is halo, X is (a-2) with q and r being 0 and Z being O, S or SO;
  • Particular compounds are those compounds of formula (I) wherein Q is iodo.
  • Preferred compounds are those compounds of formula (I) wherein Q is iodo, X-R 1 is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R 2 is a hydroxymethyl or a N-morpholinomethyl or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl.
  • Also preferred compounds are those compounds of formula (I) wherein Q is iodo, X-R 1 is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R 2 is ethyl.
  • Most preferred compounds are compounds n° 242, 255, 43, 264, 124, 249, 298, 326, 133, 241, 253, 306,328,46,105,254,256,284,296,319, 83, 88,108,109,115, 286, 299, 45, 85, 86, 244, 297, 250, 257, 307, 81, 92, 140, 143, 217, 221, 232, 245, 309, 321, 322, 31, 218, 222, 314, 8, 99, 121, 219, 233, 551, 470, 375, 483, 547, 606, 618, 662, 694, 700, 709 and 713 of table 1.
  • the present invention also relates to a method of treating warm-blooded animals suffering from HIV infection.
  • Said method comprises the administration of the therapeutically effective amount of a compound of formula (I) or any sub group thereof, a N -oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.
  • the compounds of formula (I) can be prepared according to art-known procedures.
  • compounds of formula (I) wherein X is an oxygen and R 1 a 3,5-dimethylphenyl, said compound being represented by formula (I-a) can be prepared by reacting an intermediate of formula (II) with a derivative of formula (III)
  • the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
  • the compounds of formula (I) wherein X is a sulphur can be prepared by reacting an intermediate of formula (IV) with a derivative of formula (V) in an appropriate solvent such as for example methanol, ethanol, propanol, butanol, dioxane, tetrahydrofurane, 2-methoxyethylether or toluene, and the like. This reaction can be performed at a temperature comprised between 20 and 130°C.
  • the compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
  • the compounds of formula (I) may be converted to the corresponding N -oxide forms following art-known procedures for converting a trivalent nitrogen into its N -oxide form.
  • Said N -oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chlorobenzenecarboperoxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom.
  • Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures.
  • diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods.
  • Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization of chromatographic techniques, e.g.
  • the compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl.
  • Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl.
  • Suitable protecting groups for carboxylic acid include C 1-6 alkyl or benzyl esters.
  • the protection and deprotection of functional groups may take place before or after a reaction step.
  • the compounds of the present invention show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans.
  • HIV Human Immunodeficiency Virus
  • the HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system.
  • an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally.
  • the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers.
  • HIV infection further has also been associated with peripheral neuropathy progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).
  • PDL peripheral neuropathy progressive generalized lymphadenopathy
  • ARC AIDS-related complex
  • the present compounds also show activity against HIV-1 strains that have acquired resistance to art-know non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human ⁇ -1 acid glycoprotein.
  • the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals.
  • the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase.
  • Conditions which may be prevented or treated with the compounds of the present invention include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
  • the compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions.
  • Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid sugars, kaolin, lubricants, binders, disintegrating agent and the like in the case of powders pills, capsules, and tablets.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • cyclodextrins may be included in the compositions.
  • suitable ingredients e.g. cyclodextrins
  • cyclodextrins are ⁇ , ⁇ , ⁇ -cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C 1-6 alkyl, particularly methyl, ethyl or isopropyl, e.g.
  • complexants and/or solubilizers are ⁇ -CD, randomly methylated ⁇ -CD, 2,6-dimethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxyethyl- ⁇ -CD, 2-hydroxypropyl- ⁇ -CD and (2-carboxymethoxy)propyl- ⁇ -CD, and in particular 2-hydroxypropyl- ⁇ -CD (2-HP- ⁇ -CD).
  • mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
  • the average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose.
  • the average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit.
  • the M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • IR infrared spectroscopy
  • slightly different values may be obtained for one given cyclodextrin derivative.
  • the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.
  • compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.
  • Said particles consist of a solid dispersion comprising a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers.
  • the preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:
  • the solid dispersion product is milled or ground to particles having a particle size of less than 1500 ⁇ m, preferably less than 400 ⁇ m, more preferably less than 250 ⁇ m and most preferably less than 125 ⁇ m.
  • the water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20°C in an aqueous solution at 2 % (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s.
  • suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide.
  • Preferred water-soluble polymers are Eudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.
  • cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839.
  • Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly ⁇ , ⁇ , ⁇ -cyclodextrins or the pharmaceutically acceptable derivatives thereof.
  • Substituted cyclodextrins which can be used include polyethers described in U.S. Patent 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C 1-6 alkyl, hydroxyC 1-6 alkyl, carboxy-C 1-6 alkyl or C 1-6 alkyloxycarbonylC 1-6 alkyl or mixed ethers thereof.
  • substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C 1-3 alkyl, hydroxyC 2-4 alkyl or carboxyC 1-2 alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.
  • ⁇ -cyclodextrin ethers e.g. dimethyl- ⁇ -cydodextrin as described by M. Nogradi ( Drugs of the Future, (1984) Vol. 9, No. 8, p. 577-578) and polyethers, e.g. hydroxypropyl ⁇ -cyclodextrin and hydroxyethyl ⁇ -cyclodextrin, being examples.
  • alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2.
  • a hydroxypropyl cyclodextrin may for example be formed from the reaction between ⁇ -cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.
  • a more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.
  • the ratio of the compound of formula (I) over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of the compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.
  • the compounds of formula (I) may further be convenient to formulate the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm.
  • Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (I) but do not chemically bond to said compound.
  • Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
  • Yet another interesting way of formulating the compounds of formula (I) involves a pharmaceutical composition whereby the compounds of formula (I) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
  • Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and a seal-coating polymer layer.
  • Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness.
  • examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose at two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing I to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, the weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased of the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
  • the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine.
  • the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g.
  • zidovudine (3'-azido-3'-deoxythymidine; AZT), didanosine (dideoxy inosine; ddl), zalcitabine (dideoxycytidine; ddC) or lamivudine (3'-thia-2'-3'-dideoxycytidine; 3TC) and the like; non-nucleoside reverse transcriptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, rescriptor (BHAP derivative), dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6 H dipyrido[3,2-b: 2',3'-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine)
  • indinavir ritanovir, saquinovir, ABT-378 and the like; fusion inhibitors; integrase inhibitors; or immunomodulating agents, e.g. levamisole and the like.
  • the compound of formula (I) can also be combined with another compound of formula (I).
  • the intermediate 4 (273 mg; 1 mmol) was dissolved in acetic acid (4 ml) and ethyl acetate (4 ml). At room temperature and in the dark N -iodosuccinimide (225 mg ; 1 mmol) was added in one portion. After 4 hours under stirring at room temperature, the mixture was poured into water (15 ml) and the pH of the solution was adjusted to 7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3x30 ml) were washed with brine (10 ml), dried over magnesium sulfate and evaporated to give a gum.
  • This compound was prepared starting from the di-(2,4,6-trichlorophenyl)malonate (intermediate 11) which was obtained as described by Kappe, Th., ( Mh. Chem. (1967), 98 , 874).
  • the intermediate 17 (100 mg; 0.33 mmol) was dissolved in acetic acid (2 ml) and ethyl acetate (2 ml). At room temperature and in the dark N -iodosuccinimide (75 mg; 0.33 mmol) was added in one portion. After 2.5 h under stirring at room temperature, the mixture was poured into water (5 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with CH 2 Cl 2 (3x10 ml) were washed with water (15 ml), dried over magnesium sulfate and evaporated to give a solid residue.
  • the intermediate 17 (50 mg ; 0.16 mmol) was dissolved in acetic acid (3 ml) and ethyl acetate (3 ml). At room temperature and in the dark N- bromosuccinimide (29 mg ; 0.16 mmol) was added in one portion. After 30 min. under stirring at room temperature, the mixture was poured into water (10 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3x15 ml) were dried over magnesium sulfate and evaporated to give a solid residue.
  • Table 1 lists intermediates and compounds of formula (I) which were made analogous to one of the above examples.
  • the 50% cytotoxic concentration (CC 50 in ⁇ M) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%.
  • the percent protection achieved by the compound in HIV-infected cells was calculated by the following formula: ( O D T ) HIV ⁇ ( O D C ) HIV ( O D C ) MOCK ⁇ ( O D C ) HIV expressed in %, whereby (OD T ) HIV is the optical density measured with a given concentration of the test compound in HIV-infected cells; (OD C ) HIV is the optical density measured for the control untreated HIV-infected cells; (OD C ) MOCK is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm.
  • the dose achieving 50% protection according to the above formula was defined as the 50% inhibitory concentration (IC 50 in ⁇ M).
  • the ratio of CC 50 to IC 50 was defined as the selectivity index (SI).
  • the compounds of formula (I) were shown to inhibit HIV-1 effectively. Particular IC 50 , CC 50 and SI values are listed in Table 2 hereinbelow.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • AIDS & HIV (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Quinoline Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Claims (13)

  1. Composés de formule (1)
    Figure imgb0163
    N-oxydes, sels d'addition pharmaceutiquement acceptables, amines quaternaires et formes stéréoisomères de ces composés, formule dans laquelle
    Y représente O ou S ;
    Q représente halogéno ;
    X représente un radical bivalent de formule

            -(CH2)p-     (a-1)

    ou

            -(CH2)q-Z-(CH2)r-     (a-2);

    formules dans lesquelles
    p est un nombre entier ayant une valeur de 1 à 5 ;
    q est un nombre entier ayant une valeur de 0 à 5 ;
    r est un nombre entier ayant une valeur de 0 à 5 ;
    Z représente O, S, NR7, C(=O), S(=O), S(=O)2, CHOR13, CH=CH, CH(NR7R8) ou CF2 ; et dans lesquelles chaque atome d'hydrogène peut être remplacé par un groupe alkyle en C1-4 ou hydroxyalkyle en C1-4;
    R1 représente un groupe cycloalkyle en C3-6, alcényle en C1-6, aryle ;
    R2 est choisi parmi un atome d'hydrogène et un groupe formyle ; cyano ; azido; hydroxy; oxiranyle ; amino; mono- ou di-alkyl(en C1-4)amino; formylamino ; mercapto-alkyle (en C1-6); hydrazino ; R5aR6aN-C(=O)- ; R9-N=C(R10)- ; alcényle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, di-alkyl(en C1-4)carbamoyle, [di-alkyl(en C1-4)aminoalkyl(en C1-6)]-alkyl(en C1-4)carbamoyle, [di-alkyl(en C1-4)aminoalkyl(en C1-6)]aryl-alkyl(en C1-4)carbamoyle, di-alkyloxy(en C1-4)alkyl(en C1-4)carbamoyle, cyano-alkyl(en C1-6)-alkyl(en C1-6)aminoalkyle (en C1-6), N-hydroxyimino, aryle, Het2, Het2carboxamido, Het2-alkyl(en C1-6)carbamoyle; alcynyle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)-oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2 ; alkyloxy en C1-6 ; hydroxyalkyloxy en C1-6 ; aminoalkyloxy en C1-6; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)oxy ; alkyl(en C1-6)carbonyle ; arylcarbonyle ; Het2carbonyle ; alkyl(en C1-6)oxy-carbonyle ; alkyl(en C1-6)carbonyloxy ; aryle ; aryloxy ; aryl-alkyl(en C1-6)oxy ; arylthio ; aryl-alkyl(en C1-6)thio ; mono- ou di(aryl)amino ; Het2 ; Het2oxy ; Het2thio ; Het2-alkyl(en C1-6)oxy ; Het2-alkyl(en C1-6)thio ; Het2SO2 ; Het2SO ; mono- ou di(Het2)amino ; cycloalkyle en C3-6; cycloalkyloxy en C3-6; cycloalkylthio en C3-6 ; alkylthio en C1-6; hydroxyalkylthio en C1-6 ; aminoalkylthio en C1-6 ; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-4)thio; alkyle en C1-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, carboxyle, alkyloxy en C1-6, alkylthio en C1-6, alkylsulfonyle en C1-6, alkyl(en C1-6)carbamoyl-alkyl(en C1-4)thio, hydroxyalkyloxy en C1-6, alkyl(en C1-6)oxyalkyl(en C1-6)oxy, alkyl(en C1-6)oxyalkyl(en C1-6)-thioalkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, aminocarbonyloxy, mono- ou di-alkyl(en C1-4)aminocarbonyloxy, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)oxy, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)thio, aryle, Het2, aryloxy, arylthio, aryl-alkyl(en C1-6)oxy, aryl-alkyl(en C1-6)thio, Het2-alkyl(en C1-6)oxy, Het2-alkyl(en C1-6)thio, alkyl(en C1-6)-S(=O)2-oxy, amino, mono- ou di-alkyl(en C1-4)amino, di-alkyl(en C1-6)aminoalkylthio (en C1-6), [di-alkyl(en C1-6)aminoalkyl(en C1-6)]alkyl(en C1-6)amino, di(cyano-alkyl(en C1-6))amino, alkyl(en C1-6)oxycarbonylamino, alkyl(en C1-6)oxyalkyl(en C1-6)carbonylamino, mono- ou di(aryl)-amino, mono- ou di(aryl-alkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)oxyalkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)thioalkyl(en C1-4))amino, mono- ou di(Het2-alkyl(en C1-4))amino, (Het2-alkyl(en C1-4))alkyl(en C1-4)amino, (cyano-alkyl(en C1-6))alkyl(en C1-6)amino, cycloalkylthio en C3-6, R11-(C=O)-NH-, R12-NH-(C=O)-NH-, R14- S(=O)2-NH-, alkyl(en C1-6)-P(O-R15)2=O, alkyl(en C1-6)-P(O-alkyl-(en C1-6)-O)=O ou un radical de formule
    Figure imgb0164
    où A1 représente CH ou N, et A2 représente CH2, NR13, S ou O, sous réserve que, lorsque A1 représente CH, alors A2 représente autre chose que CH2, ledit radical (c-1), (c-2) et (c-3) est éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes H, alkyle en C1-6, alkyloxy en C1-6, hydroxyalkyle en C1-4, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)-oxycarbonyl-alkyle (en C1-4), aminoalkyle en C1-6, alkyl(en C1-4)-carbonyle, arylcarbonyle, aryle, Het2, Het2-(C=O)-, hydroxy, cyano, alkyl(en C1-4)cyano, CONR16R17 où R16 et R17 représentent indépendamment H ou un groupe alkyle, mono ou di-alkyl(en C1-4)aminoalkyle, 4-hydroxy-4-phényle ou 4-cyano-4-phényle ;
    R3 est choisi parmi un atome d'hydrogène et un groupe halogéno ; formyle ; cyano ; azido ; hydroxy ; oxiranyle ; amino ; mono- ou di-alkyl(en C1-4)amino ; formylamino ; mercapto-alkyle (en C1-6) ; hydrazino ; R5aR6aN-C(=O)-; R9-N=C(R10)-; alcényle en C2-4 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)-oxycarbonyle, alkyl(en C1-6)carbonyloxy, di-alkyl(en C1-4)-carbamoyle, [di-alkyl(en C1-4)aminoalkyl(en C1-6)]-alkyl(en C1-4)-carbamoyle, [di-alkyl(en C1-4)aminoalkyl(en C1-6)]-aryl-alkyl(en C1-4)carbamoyle, di-(alkyloxy(en C1-4)alkyl(en C1-4)carbamoyle, cyano-alkyl(en C1-6)alkyl(en C1-6)amino-alkyle (en C1-6), N-hydroxyimino, aryle, Het2, Het2carboxamido, Het2-alkyl(en C1-6)carbamoyle ; alcynyle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2 ; alkyloxy en C1-6, hydroxyalkyloxy en C1-6 ; aminoalkyloxy en C1-6 ; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)oxy ; alkyl(en C1-6)carbonyle ; arylcarbonyle ; Het2carbonyle ; alkyl(en C1-6)oxycarbonyle ; alkyl(en C1-6)carbonyloxy ; aryle ; aryloxy ; aryl-alkyl(en C1-6)oxy ; arylthio ; aryl-alkyl(en C1-6)thio; mono- ou di(aryl)amino ; Het2 ; Het2oxy; Het2thio ; Het2-alkyl(en C1-6)oxy; Het2-alkyl(en C1-6)thio ; Het2SO2 ; Het2S0 ; mono- ou di(Het2)amino ; cycloalkyle en C3-6 ; cycloalkyloxy en C3-6 ; cycloalkylthio en C3-6 ; alkylthio en C1-6 ; hydroxyalkylthio en C1-6; aminoalkylthio en C1-6 ; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)thio; alkyle en C1-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, carboxyle, alkyloxy en C1-6, alkylthio en C1-6, alkylsulfonyle en C1-6, alkyl(en C1-6)carbamoyl-alkyl(en C1-6)thio, hydroxyalkyloxy en C1-6, alkyl(en C1-6)oxyalkyl(en C1-6)-oxy, alkyl(en C1-6)oxyalkyl(en C1-6)thioalkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, aminocarbonyloxy, mono- ou di-alkyl(en C1-4)aminocarbonyloxy, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)-oxycarbonyl-alkyl(en C1-6)oxy, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)thio, aryle, Het2, aryloxy, arylthio, aryl-alkyl(en C1-6)oxy, arylalkyl(en C1-6)thio, Het2-alkyl(en C1-6)oxy, Het2-alkyl(en C1-6)thio, alkyl(en C1-6)-S(=O)2-oxy, amino, mono- ou di-alkyl(en C1-6)amino, di-alkyl(en C1-6)aminoalkyl(en C1-6)thio, [di-alkyl(en C1-6)aminoalkyl(en C1-6)]alkyl(en C1-6)amino, di(cyano-alkyl(en C1-6))amino, alkyl(en C1-6)oxycarbonylamino, alkyl(en C1-6)oxyalkyl(en C1-6)-carbonylamino, mono- ou di(aryl)amino, mono- ou di(aryl-alkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)oxyalkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)thioalkyl(en C1-4))amino, mono- ou di-(Het2-alkyl(en C1-4))amino, (Het2-alkyl(en C1-4))alkyl(en C1-4)amino, (cyano-alkyl(en C1-6))alkyl(en C1-6)amino, cycloalkylthio en C3-6, R11-(C=O)-NH-, R12-NH-(C=O)-NH-, R14-S(=O)2-NH-, alkyl(en C1-6)-P(OR15)2=O, alkyl(en C1-6)-P(O-alkyl(en C1-6)-O)=O ou un radical de formule
    Figure imgb0165
    où A1 représente CH ou N, et A2 représente CH2, NR13, S ou O, sous réserve que, lorsque A1 représente CH, alors A2 représente autre chose que CH2, ledit radical (c-1), (c-2) et (c-3) est éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi H et les groupes alkyle en C1-6, alkyloxy en C1-6, hydroxyalkyle en C1-4, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)-oxycarbonyl-alkyle (en C1-4), aminoalkyle en C1-6, alkyl(en C1-4)-carbonyle, arylcarbonyle, aryle, Het1, Het1-(C=O)-, hydroxy, cyano, alkyl(en C1-4)cyano, CONR16R17 où R16 et R17 représentent indépendamment H ou un groupe alkyle, mono ou di-alkyl(en C1-4)aminoalkyle, 4-hydroxy-4-phényle ou 4-cyano-4-phényle ;

    ou bien R2 et R3 peuvent être pris conjointement pour former un radical bivalent de formule :

            (CH2)t-CH2-A3-CH2-     (d-1)

    où t est un nombre entier égal à 0, 1 ou 2 et A3 représente CH2, O, S, NR7a ou N[C(=O)R8a] et
    dans laquelle chaque atome d'hydrogène dans ladite formule (d-1) peut être substitué par un groupe halogéno, alkyle en C1-4, alkyloxy en C1-4 alkyl(en C1-4)carbonyle, halogénoalkyl(en C1-4)carbonyle ou arylcarbonyle ;
    R4 représente un atome d'hydrogène ;
    R5a et R6a représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1-4 éventuellement substitué par un groupe cyano, alkyloxy en C1-4, alkylthio en C1-4, amino, mono- ou di-alkyl(en C1-4)amino ou un radical de formule
    Figure imgb0166
    où A5 et A6 représentent chacun indépendamment CH2, NR13 ou O;
    R7, R7a et R7b représentent chacun indépendamment un atome d'hydrogène ou un groupe formyle ou alkyle en C1-4 ;
    R8, R8a et R8b représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1-4 ;
    R9 représente un atome d'hydrogène ou un groupe hydroxy, alkyloxy en C1-4, carboxyl-alkyl(en C1-4)oxy, alkyl(en C1-4)oxycarbonyl-alkyl(en C1-4)oxy, alcényloxy en C2-4, alcynyloxy en C2-4 ou aryl-alkyl(en C1-4)oxy;
    R10 représente un atome d'hydrogène ou un groupe carboxyle ou alkyle en C1-4 ;
    R11 représente un atome d'hydrogène ou un groupe alkyle en C1-4 éventuellement substitué par un groupe cyano, alkyloxy en C1-4, alkyl(en C1-4)-S(=O)2-, aryle ou Het3; alkyloxy en C1-4 ; alcényle en C2-4 ; aryl-alcényle (en C2-4) ; Het3-alcényle (en C2-4) ; alcynyle en C2-4 ; Het3-alcynyle (en C2-4), aryl-alcynyle (en C2-4) ; cycloalkyle en C3-6 ; aryle ; naphtyle ou Het3;
    R12 représente un groupe alkyle en C1-4, aryl-alkyle(en C1-4), aryle, arylcarbonyle, alkyl(en C1-4)carbonyle, alkyl(en C1-4)oxycarbonyle ou alkyl(en C1-4)oxycarbonyl-alkyle (en C1-4)
    R13 représente un atome d'hydrogène ou un groupe alkyle en C1-4 ou alkyl(en C1-4)carbonyle ;
    R14 représente un groupe alkyle en C1-4 éventuellement substitué par un groupe aryle ou Het4 ; polyhalogéno-alkyle (en C1-4) ou alcényle en en C2-4 éventuellement substitué par un groupe aryle ou Het4 ;
    R15 représente un groupe alkyle en ;
    Het1 et Het2 représentent chacun indépendamment un hétérocycle choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, isoxazolyle, thiazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, pyrrolidinyle, tétrahydrofuranyle, tétrahydrothiényle, tétrahydropyrimidinyle, imidazolidinyle, oxazolidinyle, thiazolidinyle, pipéridinyle, hexahydropyrimidinyle, pipérazinyle, hexahydropyridazinyle, morpholinyle, thiomorpholinyle, triazolyle, tétrazolyle, pyrrolyle, pyrazolyle, benzopyrrolyle, benzofuranyle, benzothiényle, benzimidazolyle, benzoxazolyle, benzothiazolyle, benzotriazolyle, indolyle, indazolyle, benzodioxanyle, quinolinyle, 2-oxo-1,2-dihydro-quinolinyle, imidazopyridinyle, dihydropyrrolyle ou dihydroisoxazolyle, ledit hétérocycle étant éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes O, S, halogéno, formyle, amino, hydroxy, cyano, alkyle en C1-4, hydroxyalkyle en C1-4, carboxy-alkyle (en C1-4), carbamoyl-alkyle (en C1-4), carbamoyl-alcoxy (en C1-4), alkyloxy en C1-4, alkyl(en C1-4)-carbonyle, alkyl(en C1-4)oxyalkyle (en C1-4), cyano-alkyle en C1-4, di- alkyl(en C1-4)amino alkyle(en C1-4), -OCONH2, alcoxy(en C1-4)alkyle(en C1-4), aryle, Het2-alkyle en C1-4, polyhalogénoalkyle en C1-4, cycloalkyle en C3-6 ou aryl-alcényle (en C2-6) ;
    Het3 représente un hétérocycle monocyclique ou bicyclique choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, thiazolyle, pyridinyle, pyrimidinyle, pyrazinyle, pyridazinyle, benzopyrrolyle, benzofuranyle, benzothiényle, benzimidazolyle, benzoxazolyle, benzothiazolyle, quinolinyle, 2-oxo-1,2-dihydroquinolinyle, pyrrolidinyle, tétrahydrofuranyle, tétrahydrothiényle, imidazolidinyle, oxazolidinyle, thiazolidinyle, pipéridinyle, hexahydropyrimidinyle, pipérazinyle, hexahydropyridazinyle ou un radical de formule
    Figure imgb0167
    où A7 ou A8 sont chacun indépendamment choisis parmi CH2 ou O ; chacun desdits hétérocycles monocycliques ou bicycliques peut éventuellement être substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle ou polyhalogénoalkyle en C1-4;
    Het4 représente un hétérocycle monocyclique choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, thiazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, ledit hétérocycle étant éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle ou polyhalogénoalkyle en C1-4 ;
    Het5 représente un groupe pyridyle, pyrimidyle, pyridazinyle, pyrazinyle, pyrrolyle, thiényle, furanyle, imidazolyle, thiazolyle, oxazolyle, tétrazolyle, pipéridinyle, morpholinyle ou pyrrolidinyle ;
    aryle représente un groupe phényle éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno ; hydroxy ; carboxyle ; cyano ; formyle ; acétyle ; nitro ; amino ; mono- ou di-alkyl(en C1-4)amino; alkyl(en C1-4)-carbonylamino ; mono- ou di-alkyl(en C1-4)aminocarbonylamino; alkyl(en C1-4)-S(=O)2-NH-; Het5(=S)-S-alkyle (en C1-4); alkyloxy en C1-6; sulfamoyle; alkyl(en C1-4)sulfamoyle; arylsulfamoyle; Het2sulfamoyle; O-P=OR15; alkyle en C1-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, nitro, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)oxyalkyl(en C1-6)oxy, alcényloxy en C2-6, alkyl(en C1-6)carbonyloxy, alkyl(en C1-6)oxycarbonylthio, N-hydroxyimino, phényle ou Het5 ; alcényle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, nitro, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5 ; alcynyle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5; phényle ; phényloxy ; phénylalkyl-(en C1-4)thio-alkyle (en C1-4) ; cycloalkyl(en C3-6)thio-alkyle (en C1-4) ou isoxazolinyle éventuellement substitué par un groupe alkyl(en C1-4)oxycarbonyle ou morpholinyl-alkyle (en C1-4) ;

    à condition d'exclure la 3-iodo-6-méthyl-4-phénoxy-2(1H)-pyridinone.
  2. Composés selon la revendication 1 dans lesquels
    Q représente un groupe halogéno ;
    X représente un radical bivalent de formule

            -(CH2)p     (a-1)

    ou

            -(CH2)q-Z-(CH2)r-     (a-2);

    formules dans lesquelles
    p est un nombre entier ayant une valeur de 1 à 5 ;
    q est un nombre entier ayant une valeur de 0 à 5 ;
    r est un nombre entier ayant une valeur de 0 à 5 ;
    Z représente O, S, NR7, C(=O), S(=O), S(=O)2, CHOR13, CH=CH, CH(NR7R8) ou CF2 ;
    et dans laquelle chaque atome d'hydrogène peut être remplacé par un groupe alkyle en C1-4 ou hydroxyalkyle en C1-4 ;
    R1 représente un groupe cycloalkyle en C3-6, aryle ;
    R2 est choisi parmi un atome d'hydrogène et un groupe formyle ; cyano ; azido ; hydroxy ; oxiranyle ; amino ; mono- ou di-alkyl(en C1-4)-amino ; formylamino ; R5aR6aN-C(=O)-; R9-N=C(R10)- ; alcényle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2 ; alcynyle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)-carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2; alkyloxy en C1-6; hydroxyalkyloxy en C1-6; aminoalkyl(en C1-6)oxy; mono- ou di-alkyl(en C1-4)amino-alkyl(en C1-6)oxy; alkyl(en C1-6)carbonyle; arylcarbonyle ; Het2-carbonyle ; alkyl(en C1-6)oxycarbonyle; alkyl(en C1-6)carbonyloxy; aryle ; aryloxy; aryl-alkyl(en C1-6)oxy; arylthio ; aryl-alkyl(en C1-6)thio; mono- ou di(aryl)amino ; Het2; Het2oxy; Het2thio; Het2-alkyl(en C1-6)oxy ; Het2-alkyl(en C1-6)thio; mono- ou di(Het2)-amino ; cycloalkyle en C3-6; cycloalkyloxy en C3-6; cycloalkylthio en C3-6; alkylthio en C1-6; hydroxyalkylthio en C1-6; aminoalkylthio en C1-6; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)thio; alkyle en C1-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, alkyloxy en C1-6, alkylthio en C1-6, hydroxyalkyloxy en C1-6, alkyl(en rC1-6)oxyalkyl(en C1-6)oxy, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, aminocarbonyloxy, mono- ou di-alkyl(en C1-6)-aminocarbonyloxy, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)oxy, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)thio, aryle, Het2, aryloxy, arylthio, aryl-alkyl(en C1-6)oxy, arylalkyl(en C1-6)thio, Het2-alkyl(en C1-6)oxy, Het2-alkyl(en C1-6)thio, alkyl(en C1-6)-S(=O)2-oxy, amino, mono- ou di-alkyl(en C1-6)amino, alkyl(en C1-6)oxycarbonylamino, alkyl(en C1-6)oxyalkyl(en C1-6)-carbonylamino, mono- ou di(aryl)amino, mono- ou di(aryl-alkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)oxyalkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)thioalkyl(en C1-4))amino, mono- ou di(Het2-alkyl(en C1-4))amino, R11-(C=O)-NH-, R12-NH-(C=O)-NH-, R14-S(=O)2-NH-, alkyl(en C1-6)-P(O-R15)2=O, alkyl(en C1-6)-P(O-alkyl(en C1-6)-O)=O ou un radical de formule
    Figure imgb0168
    dans laquelle A1 représente CH2 ou N, et A2 représente CH2, NR13, S ou O, sous réserve que, lorsque A1 représente CH2, alors A2 représente autre chose que CH2, ledit radical (c-1) et (c-2) étant éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes H, alkyle en C1-6, alkyloxy en C1-6, hydroxyalkyle en C1-4, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)oxycarbonyl-alkyle (en C1-4), aminoalkyle en C1-6, carbonyle, hydroxy, cyano, CONR16R17 où R16 et R17 représentent indépendamment H ou un groupe alkyle, mono ou di-alkyl(en C1-4)aminoalkyle, 4-hydroxy-4-phényle ou 4-cyano-4-phényle ;
    R3 est choisi parmi un atome d'hydrogène et un groupe halogéno ; formyle ; cyaho ; azido ; hydroxy ; oxiranyle ; amino ; mono- ou di-alkyl(en C1-4)amino ; formylamino ; R5aR6aN-C(=O)-; R9-N=C(R10)- ; alcényle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)-carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2 ; alcynyle en C2-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, formyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, aryle ou Het2 ; alkyloxy en C1-6; hydroxyalkyloxy en C1-6; aminoalkyloxy en C1-6; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)oxy ; alkyl(en C1-6)carbonyle; arylcarbonyle ; Het2carbonyle ; alkyl(en C1-6)oxycarbonyle ; alkyl(en C1-6)carbonyloxy ; aryle ; aryloxy ; aryl-alkyl(en C1-6)oxy ; arylthio ; aryl-alkyl(en C1-6)thio ; mono- ou di(aryl)amino ; Het2 ; Het2oxy, Het2thio ; Het2-alkyl(en C1-6)oxy ; Het2-alkyl(en C1-6)thio ; mono- ou di(Het2)amino ; cycloalkyle en C3-6; cycloalkyloxy en C3-6, cycloalkylthio en C3-6 ; alkylthio en C1-6 ; hydroxyalkylthio en C1-6 ; aminoalkylthio en C1-6 ; mono- ou di-alkyl(en C1-4)aminoalkyl(en C1-6)thio ; alkyle en C1-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, cyano, alkyloxy en C1-6, alkylthio en C1-6, hydroxyalkyloxy en C1-6, alkyl(en C1-6)oxyalkyl(en C1-6)oxy, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, aminocarbonyloxy, mono- ou di-alkyl(en C1-4)aminocarbonyloxy, alkyl(en C1-6)-oxycarbonyle, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)oxy, alkyl(en C1-6)oxycarbonyl-alkyl(en C1-6)thio, aryle, Het2, aryloxy, arylthio, aryl-alkyl(en C1-6)oxy, aryl-alkyl(en C1-6)thio, Het2-alkyl(en C1-6)-oxy, Het2-alkyl(en C1-6)thio, alkyl(en C1-6)-S(=O)2-oxy, amino, mono- ou di-alkyl(en C1-6)amino, alkyl(en C1-6)oxycarbonylamino, alkyl(en C1-6)oxyalkyl(en C1-6)carbonylamino, mono- ou di(aryl)-amino, mono- ou di(aryl-alkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)oxyalkyl(en C1-4))amino, mono- ou di(alkyl(en C1-4)thioalkyl(en C1-4))amino, mono- ou di(Het2-alkyl(en C1-4))amino, R11-(C=O)-NH-, R12-NH-(C=O)-NH-, R14-S(=O)2-NH-, alkyl(en C1-6)-P(O-R15)2-, alkyl(en C1-6)-P(O-alkyl(en C1-6)-O)=O ou un radical de formule
    Figure imgb0169
    dans laquelle A1 représente CH2 ou N, et A2 représente CH2, NR13, S ou O, sous réserve que, lorsque A1 représente CH2, alors A2 représente autre chose que CH2, ledit radical (c-1) et (c-2) étant éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi H et un groupe alkyle en C1-6, alkyloxy en C1-6, hydroxyalkyle en C1-6, alkyl(en C1-6)oxycarbonyle, alkyl(en C1-6)oxycarbonyl-alkyle (en C1-4), aminoalkyle en C1-6, carbonyle, hydroxy, cyano, CONR16R17 où R16 et R17 représentent indépendamment H ou un groupe alkyle, mono ou di-alkyl(en C1-4)aminoalkyle, 4-hydroxy-4-phényle ou 4-cyano-4-phényle;

    ou R2 et R3 peuvent être pris conjointement pour former un radical bivalent de formule

            -(CH2)t-CH2-A3-CH2-     (d-1)

    ou

            CH=CH-CH=CH-     (d-2)
    où t est un nombre entier égal à 0, 1 ou 2 et A3 représente CH2, O, S, NR7a ou N[C(=O)R8a] et où chaque atome d'hydrogène dans ladite formule (d-1) ou (d-2) peut être substitué par un groupe halogéno, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle, halogénoalkyl(en C1-4)carbonyle ou arylcarbonyle ;
    R4 représente un atome d'hydrogène ;
    R5a et R6a représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1-4 éventuellement substitué par un groupe cyano, alkyloxy en C1-4, alkylthio en C1-4, amine, mono- ou di-alkyl(en C1-4)amino ou un radical de formule
    Figure imgb0170
    où A5 et A6 représentent chacun indépendamment CH2, NR13 ou O ;
    R7, R7a et R7b représentent chacun indépendamment un atome d'hydrogène ou un groupe formyle ou alkyle en C1-4
    R8, R8a et R8b représentent chacun indépendamment un atome d'hydrogène ou un groupe alkyle en C1-4;
    R9 représente un atome d'hydrogène ou un groupe hydroxy, alkyloxy en C1-4, carboxyl-alkyl(en C1-4)oxy, alkyl(en C1-4)oxycarbonyl-alkyl(en C1-4)oxy, alcényloxy en C2-4, alcynyloxy en C2-4 ou aryl-alkyl(en C1-4)oxy,
    R10 représente un atome d'hydrogène ou un groupe carboxyle ou alkyle en C1-4;
    R11 représente un atome d'hydrogène ou un groupe alkyle en C1-4 éventuellement substitué par un groupe cyano, alkyloxy en C1-4, alkyl(en C1-4)-S(=O)2-, aryle ou Het3 ; alkyloxy en C1-4; alcényle en C2-4; aryl-alcényle (en C2-4) ; Het3-alcényle (en C2-4); alcynyle en C2-4 ; Het3-alcynyle (en C2-4), aryl-alcynyle (en C2-4) ; cycloalkyle en C3-6 ; aryle ; naphtyle ou Het3 ;
    R12 représente un groupe alkyle en C1-4, aryl-alkyle (en C1-4), aryle, arylcarbonyle, alkyl(en C1-4)carbonyle, alkyl(en C1-4)oxycarbonyle ou alkyl(en C1-4)oxycarbonyl-alkyle (en C1-4) ;
    R13 représente un atome d'hydrogène ou un groupe alkyle en C1-4 ou alkyl(en C1-4)carbonyle;
    R14 représente un groupe alkyle en C1-4 éventuellement substitué par un groupe aryle ou Het4 ; polyhalogénoalkyle en C1-4 ou alcényle en C2-4 éventuellement substitué par un groupe aryle ou Het4 ;
    R15 représente un groupe alkyle en C1-4 ;
    Het1 et Het2 représentent chacun indépendamment un hétérocycle choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, thiazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, pyrrolidinyle, tétrahydrofuranyle, tétrahydrothiényle, imidazolidinyle, oxazolidinyle, thiazolidinyle, pipéridinyle, hexahydropyrimidinyle, pipérazinyle, hexahydropyridazinyte, benzopyrrolyle, benzofuranyle, benzothiényle, benzimidazolyle, benzoxazolyle, benzothiazolyle, quinolinyle ou 2-oxo-1,2-dihydroquinolinyle, ledit hétérocycle étant éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle en C1-4 ou polyhalogénoalkyle en C1-4;
    Het3 représente un hétérocycle monocylique ou bicyclique choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, thiazolyle, pyridinyle, pyrimidinyle, pyrazinyle, pyridazinyle, benzopyrrolyle, benzofuranyle, benzothiényle, benzimidazolyle, benzoxazolyle, benzothiazolyle, quinolinyle, 2-oxo-1,2-dihydroquinolinyle, pyrrolidinyle, tétrahydrofuranyle, tétrahydrothiényle, imidazolidinyle, oxazolidinyle, thiazolidinyle, pipéridinyle, hexahydropyrimidinyle, pipérazinyle, hexahydropyridazinyle ou un radical de formule
    Figure imgb0171
    où A7 ou A8 sont chacun indépendamment choisis parmi CH2 ou O ; chacun desdits hétérocycles monocycliques ou bicycliques peut éventuellement être substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle ou polyhalogénoalkyle en C1-4 ;
    Het4 représente un hétérocycle monocyclique choisi parmi les groupes pyrrolyle, furanyle, thiényle, imidazolyle, oxazolyle, thiazolyle, pyridyle, pyrimidinyle, pyrazinyle, pyridazinyle, ledit hétérocycle étant éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno, hydroxy, alkyle en C1-4, alkyloxy en C1-4, alkyl(en C1-4)carbonyle ou polyhalogénoalkyle en C1-4 ;
    Het5 représente un groupe pyridyle, pyrimidyle, pyridazinyle, pyrazinyle, pyrrolyle, thiényle, furanyle, imidazolyle, thiazolyle ou oxazolyle ;
    aryle représente un groupe phényle éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno ; hydroxy; carboxyle ; cyano ; formyle ; nitro ; amino ; mono- ou di-alkyl(enC1-4)amino; alkyl(en C1-4)carbonylamino ; mono- ou di-alkyl(en C1-4)aminocarbonylamino ; alkyl(en C1-4)-S(=O)2NH-; alkyloxy en C1-6, alkyle en C1-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)oxyalkyl(en C1-6)oxy, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5 ; alcényle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5; alcynyle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)-carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5 ; phényle ou phényloxy.
  3. Composés selon la revendication 1 dans lesquels
    Q représente un groupe halogéno,
    X est (a-2), où q et r sont égaux à 0 et Z représente O, S ou SO ;
    R1 représente un groupe phényle éventuellement substitué par un, deux ou trois substituants choisis chacun indépendamment parmi les groupes halogéno ; hydroxy ; carboxyle; cyano ; formyle ; nitro ; amino ; mono- ou di-alkyl(en C1-4)amino; alkyl(en C1-4)carbonylamino ; mono- ou di-alkyl(en C1-4)aminocarbonylamino ; alkyl(en C1-4)-S(=O)2-NH- ; alkyloxy en C1-6, alkyle en C1-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-4, alkyl(en C1-6)oxyalkyl(en C1-6)oxy, alkyl(en C1-6)-carbonyloxy, N-hydroxyimino, phényle ou Het5; alcényle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5; alcynyle en C2-6 éventuellement substitué par un groupe halogéno, hydroxy, cyano, formyle, amino, mono- ou di-alkyl(en C1-4)amino, alkyl(en C1-6)oxycarbonyle, alkyloxy en C1-6, alkyl(en C1-6)carbonyle, alkyl(en C1-6)carbonyloxy, N-hydroxyimino, phényle ou Het5; phényle ou phényloxy ;
    R2 est choisi parmi les groupes formyle ; alkyl(en C1-6)oxycarbonylalkyle ; Het2 ; Het2-alkyle (en C1-6) ; alkylthio en C1-6 ; alkyle en C1-6 éventuellement substitué par un ou deux substituants choisis chacun indépendamment parmi les groupes hydroxy ou halogéno ;
    R3 est choisi parmi les groupes formyle ; alkyle en C1-6 éventuellement substitué par un ou deux groupes alkyloxy en C1-6 ;
    R4 représente un atome d'hydrogène.
  4. Composés selon l'une quelconque des revendications 1 et 3 dans lesquels Q représente un groupe iodo.
  5. Composés selon l'une quelconque des revendications 1 à 4 dans lesquels Q représente un groupe iodo, X-R1 représente un groupe 3,5-diméthylphénylthio ou un groupe 3,5-diméthylphényloxy et R2 représente un groupe hydroxyméthyle ou un groupe N-morpholinométhyle, ou un groupe 3-phénylpropyle ou un groupe furan-2-yl-méthylthiométhyle.
  6. Composés selon l'une quelconque des revendications 1 à 5 dans lesquels Q représente un groupe iodo, X-R1 représente un groupe 3-(2-cyanovinyl)-5-iodophényloxy ou 5-bromo-3-(2-cyanovinyle) et R2 représente un groupe éthyle.
  7. Composés selon l'une quelconque des revendications 1 à 4 dans lesquels les composés sont énumérés dans le tableau suivant :
    Figure imgb0172
    Figure imgb0173
    Figure imgb0174
    Figure imgb0175
    Figure imgb0176
    Figure imgb0177
    Figure imgb0178
    Figure imgb0179
    Figure imgb0180
    Figure imgb0181
    Figure imgb0182
    Figure imgb0183
    Figure imgb0184
    Figure imgb0185
    Figure imgb0186
    Figure imgb0187
    Figure imgb0188
    Figure imgb0189
    Figure imgb0190
    Figure imgb0191
    Figure imgb0192
    Figure imgb0193
    Figure imgb0194
    Figure imgb0195
    Figure imgb0196
    Figure imgb0197
  8. Utilisation d'un composé selon l'une quelconque des revendications 1 à 7 pour la fabrication d'un médicament destiné à traiter des sujets soufrant d'une infection par le virus du syndrome immunodéficitaire acquis.
  9. Composition pharmaceutique comprenant un véhicule pharmaceutiquement acceptable et une quantité à activité thérapeutique d'un composé tel que défini dans l'une quelconque des revendications 1 à 7.
  10. Procédé de préparation d'une composition pharmaceutique telle que définie dans la revendication 9, caractérisé en ce que l'on mélange intimement une quantité à efficacité thérapeutique d'un composé tel que défini dans l'une quelconque des revendications 1 à 5 avec un véhicule pharmaceutiquement acceptable.
  11. Association d'un composé de formule (I) telle que définie dans la revendication 1 et d'autres composés antirétroviraux.
  12. Produit contenant (a) un composé de formule (I) telle que définie dans la revendication 1 et (b) un autre composé antirétroviral sous forme de préparation associée destinée à une utilisation simultanée, séparée ou séquentielle dans un traitement anti-VIH.
  13. Composition pharmaceutique comprenant un véhicule pharmaceutiquement acceptable et, comme principes actifs, (a) un composé de formule (I) telle que définie dans la revendication 1 et (b) un autre composé antirétroviral.
EP01980812A 2000-09-19 2001-09-18 Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih Expired - Lifetime EP1318995B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP01980812A EP1318995B1 (fr) 2000-09-19 2001-09-18 Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP00402583 2000-09-19
EP00402583 2000-09-19
EP01980812A EP1318995B1 (fr) 2000-09-19 2001-09-18 Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih
PCT/IB2001/002082 WO2002024650A2 (fr) 2000-09-19 2001-09-18 Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih

Publications (2)

Publication Number Publication Date
EP1318995A2 EP1318995A2 (fr) 2003-06-18
EP1318995B1 true EP1318995B1 (fr) 2006-03-08

Family

ID=8173871

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01980812A Expired - Lifetime EP1318995B1 (fr) 2000-09-19 2001-09-18 Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih

Country Status (7)

Country Link
US (1) US7115608B2 (fr)
EP (1) EP1318995B1 (fr)
JP (1) JP2004509867A (fr)
AT (1) ATE319706T1 (fr)
AU (1) AU2002212598A1 (fr)
DE (1) DE60117839T2 (fr)
WO (1) WO2002024650A2 (fr)

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040235761A1 (en) * 2001-08-14 2004-11-25 Yousuke Furuta Novel virus proliferaton inhibition/virucidal method and novel pyradine nucleotide/pyradine nucleoside analogue
CA2824106A1 (fr) * 2003-08-29 2005-03-10 Ono Pharmaceutical Co., Ltd. Compose capable de se lier au recepteur s1p
EP1516873A1 (fr) * 2003-09-22 2005-03-23 Facultés Universitaires Notre-Dame de la Paix Dérives de 2-pyridinone présentant des propriétés inhibitrices du VIH
WO2006012624A2 (fr) * 2004-07-21 2006-02-02 The Regents Of The University Of California Agents de reticulation fondes sur un mecanisme
CN103102303B (zh) * 2004-12-31 2015-10-28 雷迪博士实验室有限公司 作为cetp抑制剂的苄胺衍生物
US7728013B2 (en) 2005-05-10 2010-06-01 Intermune, Inc. Method of modulating stress-activated protein kinase system
DE602006020293D1 (de) * 2005-08-29 2011-04-07 Vertex Pharma 3,5-disubstituierte pyrid-2-one, die als hemmer der tec-familie von nicht-rezeptor tyrosin-kinasen nützlich sind
JP5539216B2 (ja) * 2007-11-20 2014-07-02 メルク・シャープ・アンド・ドーム・コーポレーション 非ヌクレオシド系逆転写酵素阻害剤
CL2009000949A1 (es) * 2008-04-21 2010-12-24 Novartis Ag Compuestos derivados de 1,2,3,5-tetrahidro-indolizina, 6,7,8,9-tetrahidro-4h-quinolizina sustituidos, inhibidores de la actividad de cinasa de mek; su composicion farmaceutica; su uso para el tratamiento de enfermedades hiperproliferativas, tal como cancer e inflamaciones.
CA2722159C (fr) 2008-04-24 2016-04-05 Newlink Genetics Corporation Inhibiteurs de l'ido
ES2567283T3 (es) 2008-06-03 2016-04-21 Intermune, Inc. Compuestos y métodos para tratar trastornos inflamatorios y fibróticos
WO2010026075A1 (fr) * 2008-09-04 2010-03-11 F. Hoffmann-La Roche Ag Dérivés de pyridine en tant qu’inhibiteurs de la transcriptase inverse de vih-1
CN103288719A (zh) * 2012-03-05 2013-09-11 苏州欧凯医药技术有限公司 非核甘艾滋病毒抑制物-吡啶酮类先导体的合成
WO2014043252A2 (fr) 2012-09-11 2014-03-20 Rutgers, The State University Of New Jersey Hydroxypyridones, hydroxypyrimidinones et hydroxypyridazinones thérapeutiques
AR092742A1 (es) 2012-10-02 2015-04-29 Intermune Inc Piridinonas antifibroticas
TW201441193A (zh) 2012-12-06 2014-11-01 Kyowa Hakko Kirin Co Ltd 吡啶酮化合物
JP6466461B2 (ja) 2014-02-03 2019-02-06 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Ｒｏｒガンマのジヒドロピロロピリジン阻害剤
CA2943363A1 (fr) 2014-04-02 2015-10-08 Intermune, Inc. Pyridinones anti-fibrotiques
EP3180335B1 (fr) 2014-08-11 2021-05-05 Angion Biomedica Corporation Inhibiteurs de cytochrome p450 et leurs utilisations
AU2015333610B2 (en) 2014-10-14 2019-11-07 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10287282B2 (en) 2014-12-31 2019-05-14 Angion Biomedica Corp. Methods and agents for treating disease
WO2016185026A1 (fr) * 2015-05-20 2016-11-24 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés et composition pharmaceutique pour la modulation de la polarisation et de l'activation des macrophages
ES2856931T3 (es) 2015-08-05 2021-09-28 Vitae Pharmaceuticals Llc Moduladores de ROR-gamma
BR112018010018A2 (pt) 2015-11-20 2018-11-21 Vitae Pharmaceuticals Inc moduladores de ror-gama
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
CN106279011A (zh) * 2016-08-16 2017-01-04 成都百事兴科技实业有限公司 一种2,4‑二羟基‑6‑甲基烟酸乙酯的制备方法
WO2018125983A1 (fr) 2016-12-30 2018-07-05 Mitobridge, Inc. Dérivés d'oxopyridine utiles en tant qu'inhibiteurs de la semialdéhyde décarboxylase d'aminocarboxymuconate (acmsd)
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
MX2020000887A (es) 2017-07-24 2020-07-22 Vitae Pharmaceuticals Llc Inhibidores de ror?.
CN113234084B (zh) * 2021-05-18 2023-05-05 云南民族大学 一种鹤庆唐松草中具有抗轮状病毒活性的化合物及其制备方法
AU2023276599A1 (en) 2022-05-25 2024-12-05 Imagenebio, Inc. Mek inhibitors and uses thereof

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017499A (en) * 1976-04-05 1977-04-12 Sandoz, Inc. 6H(1)-Benzopyrano(3,2-c)quinolines
DE3406329A1 (de) * 1984-02-22 1985-08-22 Merck Patent Gmbh, 6100 Darmstadt Pyridone
IL98526A0 (en) * 1990-06-18 1992-07-15 Merck & Co Inc Pyridones,processes for their preparation and pharmaceutical compositions containing them
FR2737496B1 (fr) * 1995-07-31 1997-12-19 Centre Nat Rech Scient 4-aryl-thio-pyridin-2(1h)-ones, medicaments les contenant et leurs utilisations dans le traitement de maladies liees aux vih 1 et 2
DE19544098A1 (de) * 1995-11-27 1997-05-28 Hoechst Schering Agrevo Gmbh Cycloalkylmethyl- und Cycloalkylidenmethyl-Pyridine, Verfahren zu ihrer Herstellung, diese enthaltende Mittel und ihre Verwendung als Schädlingsbekämpfungsmittel und Fungizide
DE19613591A1 (de) * 1996-04-04 1997-10-09 Hoechst Ag Substituierte-Chinolin-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung
NZ335992A (en) * 1996-12-05 2001-09-28 Amgen Inc Substituted pyrimidinone and pyridone compounds and methods of use
DE19732330C2 (de) * 1997-07-28 2001-04-19 Koenig & Bauer Ag Antrieb für eine Druckeinheit
DE19755316C2 (de) * 1997-12-12 1999-10-07 Koenig & Bauer Ag Antrieb für Zylinder einer Druckeinheit
US6451822B1 (en) * 1998-04-27 2002-09-17 Centre National De La Recherche Scientifique 3-(Amino- or aminoalkyl)pyridinone derivatives and their use for the treatment of HIV related diseases
CA2333643A1 (fr) * 1998-06-30 2000-01-06 James D. Rodgers Quinoline-2(1h)-ones substituees utiles comme inhibiteurs de la transcriptase inverse du vih
GB9930061D0 (en) * 1999-12-20 2000-02-09 Glaxo Group Ltd Quinolone compounds for use in treating viral infections
EP1318914B1 (fr) * 2000-09-20 2012-08-15 Koenig & Bauer Aktiengesellschaft Procédé de fonctionnement d'une unité d'impression.

Also Published As

Publication number Publication date
WO2002024650B1 (fr) 2002-11-14
DE60117839D1 (de) 2006-05-04
WO2002024650A2 (fr) 2002-03-28
US7115608B2 (en) 2006-10-03
DE60117839T2 (de) 2006-11-23
EP1318995A2 (fr) 2003-06-18
WO2002024650A3 (fr) 2002-08-08
JP2004509867A (ja) 2004-04-02
ATE319706T1 (de) 2006-03-15
US20040229847A1 (en) 2004-11-18
AU2002212598A1 (en) 2002-04-02

Similar Documents

Publication Publication Date Title
EP1318995B1 (fr) Derives de pyridinone et de pyridinethione presentant des proprietes inhibitrices du vih
JP5230050B2 (ja) Ｈｉｖ複製阻害剤
KR100658489B1 (ko) Ｈｉｖ 복제를 억제하는 피리미딘
EP1419152B1 (fr) Derives de pyrimidines inhibiteurs de vih
AU2002329238A1 (en) HIV inhibiting pyrimidines derivatives
US20040102456A1 (en) Hiv inhibiting pyrazinone derivatives
US7015221B2 (en) 2,4-disubstituted triazine derivatives
AU2002315251B2 (en) HIV inhibiting pyrazinone derivatives
MXPA01003646A (en) Hiv replication inhibiting pyrimidines
AU2002315251A1 (en) HIV inhibiting pyrazinone derivatives
HK1038232B (en) 2,4-disubstituted triazine derivatives with anti hiv activity

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030407

AK Designated contracting states

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20040601

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20060308

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

Ref country code: LI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

Ref country code: CH

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60117839

Country of ref document: DE

Date of ref document: 20060504

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060608

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060608

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060619

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060808

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060918

ET Fr: translation filed
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060930

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20061211

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060609

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20060918

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20060308

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20100826

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20101018

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20100909

Year of fee payment: 10

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20110918

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20120531

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60117839

Country of ref document: DE

Effective date: 20120403

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120403

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110930

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20110918